Cardiovascular disease is the number 1 cause of death in the United States. Incomplete vascular repair resulting from inappropriate growth of vascular smooth muscle cells (SMC) coupled with deficient reendothelialization is a major limitation of interventional therapies. Approaches are being developed that aim to either inhibit SMC hyperplasia or stimulate reendothelialization. However, it has become clear that regulation of these two processes is difficult to achieve independently. A principal reason for this likely lies in the relationship between 2 of the key growth factors involved in these processes, basic fibroblast growth factor (FGF2) and vascular endothelial growth factor (VEGF). While excessive FGF2 activity is thought to contribute to SMC hyperplasia, insufficient VEGF activity is believed to underlie deficient reendothelialization. Our results have revealed significant similarities in the manner by which heparan sulfate proteoglycans (HSPG) modulate these 2 growth factors, yet we have also identified distinctions. These finding have led us to hypothesize that HSPG structure and distribution dictate the vascular cell response to FGF2 and VEGF. Thus, it is the goal of the present proposal to identify the specific elements underlying HSPG modulation of FGF2 and VEGF within vascular cells (smooth muscle and endothelial), such that this information can eventually be exploited to effectively stimulate vascular repair without restenosis. The specific aims of this proposal are: 1. Identify the pH sensitive heparin-binding domain within VEGF121/165 and characterize its function. 2. Define the role of HSPG and lipid rafts in endothelial and smooth muscle cells on VEGF121/165 and FGF2 binding, trafficking, and activity. 3. Determine the specific heparan sulfate structures required for VEGF and FGF2 binding within endothelial HSPG. 4. Evaluate the role of syndecan 4 and lipid rafts in the vascular response to VEGF and FGF2 in vivo. We plan to utilize a multidisciplinary approach involving a combination of molecular, biochemical, biophysical, and theoretical methods along with animal studies to expose the complexities of HSPG modulation of FGF2 and VEGF. These studies will have wide ranging impact on vascular biology and will likely reveal previously undefined mechanisms of growth factor control that could help identify targets for clinical modulation.